9,10-Seco-steroid preparation

ABSTRACT

A process for the preparation of 9,10-seco-steroids of the formula ##STR1## wherein R 1  and R 2  independently are hydrogen, amino, OR 5 , OCOR 6  or NHCOR 5  wherein R 5  is hydrogen or lower alkyl and R 6  is lower alkyl or phenyl; R 3  is lower alkyl; R 4  is oxo, ##STR2##  wherein R 13  is lower alkyl, lower alkoxy - lower alkylene, tetrahydropyranyl or tetrahydrofuryl, R 14  is lower alkyl or aryl and R 15  and R 16  are lower alkyl or taken together form lower alkylene or arylene, and n is 1 or 2 is disclosed. The 9,10-seco-steroids of this invention are useful intermediates for the preparation of steroids.

This is a division of application Ser. No. 533,101 filed Dec. 16, 1974,now abandoned.

DESCRIPTION OF THE INVENTION

The present invention relates to novel 9,10-seco-steroids and toprocesses for the preparation thereof. More specifically, the presentinvention relates to 9,10-seco-steroids represented by the generalformula ##STR3## wherein R¹ and R² independently are hydrogen, amino,OR⁵, OCOR⁶ or NHCOR.sup. 5 wherein R⁵ is hydrogen or lower alkyl and R⁶is lower alkyl or phenyl; R³ is lower alkyl; R⁴ is oxo, ##STR4## whereinR¹³ is lower alkyl, lower alkoxy-lower alkylene, tetrahydropyranyl ortetrahydrofuryl, R¹⁴ is lower alkyl or aryl and R¹⁵ and R¹⁶ are loweralkyl or taken together form lower alkylene or arylene, and n is 1 or 2.

As used throughout the specification and appended claims, the term"lower" denotes a group having a carbon skeleton containing up to andincluding 7 carbon atoms; the term "alkyl" signifies a monovalentradical derived from a saturated branched or straight chain hydrocarbon;the term "alkoxy" denotes a radical derived from an alcohol having asaturated branched or straight chain hydrocarbon residue by abstractionof the proton bound to oxygen; the term "alkylene" signifies a divalentradical derived from a saturated branched or straight chain hydrocarbon;and the term "arylene" denotes a divalent radical derived from anaromatic hydrocarbon. Examples of lower alkyl groups are methyl, ethyl,propyl, isopropyl and tert.-butyl, the preferred lower alkyl groupsbeing methyl, ethyl and tert.-butyl. Examples of lower alkoxy-loweralkylene groups are methoxymethylene and2-methoxy-2,2-dimethylmethylene. Examples of lower alkylene groups areethylene, propylene and 2,2-dimethylpropylene. An example of an arylgroup is phenyl and examples of arylene groups are 1,2-phenylene or3,4-naphthylene. The configuration of the various substituents attachedto the 9,10 -seco-steroids of this invention represented by structuralformulas throughout the specification and appended claims is signifiedby three notations. With respect to substituents attached to thebicyclic system, a solid line (--) denotes a substituent attached in thebeta-configuration, i.e., a substituent attached in the configurationabove the plane of the paper; a dotted line (----) denotes a substituentattached in the alpha-configuraton i.e., a substituent attached in theconfiguration below the plane of the paper, and a wiggly line ( )denotes a substituent in either the alpha- or beta-configuration. Withrespect to substituents attached to the 1- or alpha-position of thephenethyl side-chain, a wiggly line ( ) denotes a substituent attachedin either one of the two possible stereochemical configurations.

The alkyl group bound to the 13-position of the 9,10-seco-steroidnucleus has been arbitrarily assigned the beta-configuration, which isconsistent with the absolute stereochemistry of the products describedin the examples. The formulas presented in the specification andappended claims, however, are not limiting. It is intended that theseformulas represent both enantiomeric series and mixtures thereof, forexample, racemic mixtures.

Preferred compounds of formula I are those wherein R³ is methyl orethyl, R⁴ is beta-tert.butoxy or beta-methoxymethyleneoxy, R¹ is methoxyor amino, R² is hydrogen or methoxy, and n is 1.

The 9,10 -seco-steroids of formula I are prepared by condensing abicyclic 2-methylene ketone of formula II ##STR5## wherein R³, R⁴ and nare as hereinbefore defined, with an alpha-nitrotoluene of formula III##STR6## wherein R⁷ and R⁸ independently and respectively are R¹ and R²,nitro, benzyloxy, diphenylmethoxy or triphenylmethoxy and R⁹ ishydrogen, cyano or COOR¹⁰ wherein R¹⁰ is lower alkyl or benzyl, in thepresence of a basic catalyst to give a 6-nitro-seco-steroid of formulaIV ##STR7##

wherein R³, R⁴ , R⁷, R⁸, R⁹ and n are as hereinbefore defined,

followed by saponification and decarboxylation of the 6-cyano or6-alkoxycarbonyl or 6-benzyloxycarbonyl group, if present, andhydrogenolysis of the 6-nitro group in the presence of a noble metal ornickel catalyst.

The condensation of a bicyclic ketone of formula II with analpha-nitrotoluene of formula III is performed in a suitable organicsolvent, for example, a hydrocarbon such as pentane, hexane, benzene ortoluene, an ether such as diethyl ether, dioxane or tetrahydrofuran, analcohol such as methanol, ethanol or tert.-butanol or an amide such asdimethylformamide or dimethylacetamide, at room or elevated temperature,preferably at or about room temperature, in the presence of a basiccatalyst. A wide variety of bases may be employed. For example, metalalcoholates such as sodium methylate or sodium ethylate, metal hydridessuch as sodium hydride, tertiary amines such as triethylamine andquaternary ammonium hydroxides such as benzyltrimethylammonium hydroxidemay be utilized. While the amount of base employed is not critical,catalytic amounts of base are preferred, catalytic amounts of base of 1to 10 mol percent being particularly preferred.

In an alternate embodiment of the invention, 6-nitro-seco-steroids offormula IV are prepared by adding the preformed alkali metal salt,preferrably the sodium salt, or an alpha-nitrotoluene of formula III,prepared by treating an alpha-nitrotoluene of formula III with an alkalimetal alcoholate such as sodium methylate or an alkali metal hydridesuch as sodium hydride and a suitable solvent, for example, an alcoholsuch as methanol or an amide such as dimethylformamide ordimethylacetamide to a solution of a bicyclic alpha-methylene ketone offormula II also in a suitable alcoholic solvent such as methanol oramidic solvent such as dimethylformamide or dimethylacetamide.

In another alternate embodiment of the invention, the bicyclicalpha-methylene ketone of formula II is generated in situ, i.e., thecompound of formula II is formed in the reaction mixture. In thisembodiment of the invention, a bicyclic ketone of formula IIa ##STR8##wherein R³ is lower alkyl; ##STR9## wherein R¹³ is lower alkyl, loweralkoxy-lower alkylene, tetrahydropyranyl or tetrahydrofuryl, R¹⁴ islower alkyl or aryl and R¹⁵ and R¹⁶ are lower alkyl or taken togetherform lower alkylene or arylene; X is OR¹¹, N(R¹²)₂, SR¹¹, N⁺(R¹²)₃,##STR10## or S(R¹²)₂ wherein R¹¹ is hydrogen, lower alkyl, acetyl orbenzoyl, R¹² is lower alkyl, and m is 1 or 2,

is treated with an alpha-nitrotoluene of formula III under theconditions utilized for the condensation of compounds of formulas II andIII in the presence of a base to give a compound of formula IV.

Cyano or ester groups attached to the 6-position of 9,10-seco-steroidsof formula IV are saponified by alkali, for example sodium hydroxide, tothe corresponding carboxylate salts which readily decarboxylate upontreatment with a mineral acid, such as hydrochloric acid, to6-nitro-seco-steroids of formula IVa ##STR11## wherein R³, R⁴, R⁷, R⁸and n are as hereinbefore defined.

The conversion of 6-nitro-9,10-seco-steroids of formula IVa to9,10-seco-steroids of formula I is effected by hydrogenation in thepresence of a hydrogenation catalyst. In this embodiment of theinvention, a solution of a 6-nitro-9,10-seco-steroid of formula IVa anda suitable inert organic solvent, for example, a hydrocarbon such aspentane, hexane, benzene or toluene, an ether such as diethyl ether,dioxane or tetrahydrofuran, an alcohol such as methanol, ethanol ortert.butanol or an amide such as dimethylformamide or dimethylacetamide,dimethylformamide being preferred, is hydrogenated in the presence of anoble metal or nickel catalyst. As the noble metal catalyst, palladiumis preferred, palladium/carbon is especially preferred and 5 to 10%palladium carbon is particularly preferred. As the nickel catalyst,Raney nickel is preferred. During the course of the hydrogenolysis ofthe 6-nitro group of compounds of formula IVa, nitro groups affixed tothe aromatic A-ring are reduced to amino groups and benzyloxy,diphenylmethoxy and triphenylmethoxy also attached to the aromaticA-ring are cleaved to phenols.

The aforementioned hydrogenolysis of compounds of formula IVa may beaccomplished by employing solutions of compounds of formula IVa obtaineddirectly in the condensation step of compounds of formulas II and IIIwherein R⁹ of formula II is hydrogen or thesaponification-decarboxylation step of compounds of formula IV whereinR⁹ is cyano or COOR¹⁰ wherein R¹⁰ is lower alkyl or benzyl

9,10-seco-steroids of formula I wherein R¹ and R² independently arehydrogen, amino, OR⁵, OCOR⁶ or NHCOR⁵ wherein R⁵ is hydrogen or loweralkyl and R⁶ is lower alkyl or phenyl; R³ is lower alkyl; R⁴ is oxo,##STR12## wherein R¹³ is lower alkyl, lower alkoxy-lower alkylene,tetrahydropyranyl or tetrahydrofuryl, R¹⁴ is lower alkyl or takentogether form lower alkylene or arylene, and n is 1 or 2, with theproviso that R⁵ is hydrogen when n is 1 or R² is a group other thanhydrogen, are novel compounds and are included within the scope of theinvention.

The 9,10-seco-steroids of this invention are useful intermediates forthe preparation of steroids, especially steroids of the estrone series.As depicted in Chart A, steroids of Formulas V and VI wherein R¹, R² ,R³, R⁴ and n are as hereinbefore defined, are prepared by cyclization ofcompounds of formula I followed by reduction of the 9,11-double bond ofcompounds of formula V. Specifically, compounds of formula I arecyclized to compounds of formula V in the presence of a mineral acid,for example hydrochloric acid, or an organic acid, for examplep-toluenesulfonic acid, the preferred acid concentration being 0.5N to4N, at 0° to 30°, and compounds of formula V are reduced to compounds offormula VI by hydrogen in the presence of a palladium/carbon catalyst,preferably a 5% palladium/carbon catalyst. ##STR13##

The following Examples further illustrate the present invention, whichis not restricted thereto.

In the following examples, NMR denotes nuclear magnetic resonance.

EXAMPLE 1

a. 7.5 g of (+)- 1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one were added to asolution prepared by the addition of 5.01 g of m-methoxy-α-nitrotolueneto 60 ml of 0.05-N methanolic sodium methylate solution and theresulting light-yellow solution was allowed to stand at room temperatureunder an argon atmosphere. Crystals precipitated. The suspension wascooled to 0° C., filtered under vacuum and the residue was washed with20 ml of ice-cold methanol and dried at 50° C. and 11 Torr for 2 hoursto give 6.65 g of colorless crystals melting at 111°-112° C.Recrystallization from 60 ml of isopropyl ether gave 5.3 g of pureepimer of17β-tert.butoxy-3-methoxy-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-oneas colorless prisms melting at 116°-117° C.; [α]_(D) ²⁵ = +13.8 (c = 1.0in chloroform); NMR (CDCl₃): 1.07 ppm (3H, singlet) C-18-CH₃.

The combined filtrates were treated with 0.2 ml of glacial acetic acidand concentrated under a water-jet vacuum on a bath at 40° C. Theresidue was dissolved in 80 ml of ether and the solution was washed withwater, dried over anhydrous sodium sulphate and concentrated under awater-jet vacuum on a bath 40° C. The residue, 6.4 g of a yellow oil,was dissolved in 20 ml of ether and the solution was added to a column(0.06-2 mm) of 640 g of silica gel prepared with 9 parts by volume ofn-hexane and 1 part by volume of ether. Elution with a total of 3.5 l.of the same solvent mixture gave, after concentration, 0.4 g of residuewhich consisted mainly of a dimer of the methylene ketone. By elutionwith a total of 8 l. of a mixture of 7.5 parts by volume of n-hexane and2.5 parts by volume of ether, there were obtained, after concentration(finally on a bath at 50° C. and 0.01 Torr), 5.0 g of a yellow-coloredoil. According to the thin-layer chromatogram and the NMR spectrum, thisoil consists of a ca 1:1 mixture of the aforementioned crystalline nitrocompound of melting point 116°-117° C. and its oily C-6 epimer; NMR(CDCl₃): 0.64 ppm (3H, singlet) C--18--CH₃.

b. A solution of 4.03 g of (+)-17β-tert.butoxy-3-methoxy-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-one(crystalline epimer) in 40 ml of dimethlformamide was treated with 4.0 gof 5% palladium/carbon and the system was evacuated and subsequentlyshaken in a hydrogen atmosphere. After 3 hours the hydrogen uptakeamounted to only 1 ml per minute. After a further hour, thehydrogenation was stopped. The catalyst was filtered under vacuum,washed with 20 ml of methylene chloride and the filtrate was poured onto 400 ml of water. The resulting emulsion was extracted with a total of150 ml of ether. The ethereal extract was washed first with 20 ml of0.5-N hydrochloric acid, then with water and dried over anhydrous sodiumsulphate. After filtration and concentration, finally at 50° C. and 0.01Torr, there were obtained 3.5 g of an oil. The oil was dissolved in asmall amount of benzene and added to a column of 200 g of silica gelprepared in benzene. Elution with a mixture of 49 parts by volume ofbenzene and 1 part by volume of ethyl acetate initially gave slightamounts of an apolar oil and subsequently 3.2 g of residue which, afterdistillation in a bulb-tube, yielded 2.9 g of(+)-17β-tert.butoxy-3-methoxy-9,10-seco-estra-1,3,5(10)-trien-9-one as aslightly yellow colored oil of boiling point 190°-200° C./0.01 Torr;[α]_(D) ²⁵ = +26.3° (c = 1.01 in chloroform).

EXAMPLE 2

To 20 ml of 1-N methanolic sodium methylate solution were added dropwiseat 0° C. with stirring and gassing with argon, firstly 3.34 g ofm-methoxy-α-nitrotoluene and then, within 15 minutes, a solution of 5.0g of (+)-1β-t-butoxy-3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one in 30 ml ofmethanol. The cooling bath was removed and the yellowish solution wasstirred at room temperature under argon for 4 hours. After this time,all of the methylene ketone had reacted according to thin-layerchromatography. The solution was treated with 1.25 ml of glacial aceticacid and concentrated under a water-jet vacuum on a bath at 40° C. Theresidue was taken up in 100 ml of ether. The solution was washed withwater and dried over anhydrous sodium sulphate. After concentration on abath at 40° C., finally at 11 Torr, there were obtained 8.7 g of abrownish oil. The oil was dissolved in 15 ml of ether andchromatographed on a column of 350 g of silica gel prepared with 19parts by volume of n-hexane and 1 part by volume of ether. The columnwas first eluted with 4 l of the same solvent mixture. The eluatecontained m-methoxy-α-nitrotoluene and dimers of (+)-1β-tert.butoxy-3aα,6,7,7 a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one. Subsequentelution with 1.5 l. of a mixture consisting of 9 parts by volume onn-hexane and 1 part by volume of ether yielded 2.2 g of the C-6 epimericmixture of(+)-17β-tert.butoxy-3-methoxy-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-one.After crystallization from 10 ml of isopropyl ether, there were obtained1.2 g of crystals melting at 115°-116° C. Further elution with 1.5 l. ofa mixture consisting of 4 parts by volume of n-hexane and 1 part byvolume of ether gave a further 1.8 g of the epimer mixture (1:1according to NMR).

EXAMPLE 3

To a solution of 5.01 g of m-methoxy-α-nitrotoluene in 30 ml of benzenewere added with stirring at room temperature firstly 4.22 ml oftriethylamine and then 7.32 g of (+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one. The yellowishsolution was left under an argon atmosphere at room temperature for 68hours, after which time the methylene ketone could no longer be detectedin the thin-layer chromatogram. The solution was washed with a total of80 ml of ice-cold 1-N hydrochloric acid, with 30 ml of a 5% sodiumbicarbonate solution and water. After drying over anhydrous sodiumsulphate and concentration, finally at 50° C. and 14 Torr, 14 g of abrown oil were obtained. This was dissolved in 20 ml of ether and addedto a column of 420 g of silica gel prepared with n-hexane. Elution with5.5 l. of a mixture consisting of 19 parts by volume of n-hexane and 1part by volume of ether gave 3.1 g of an oily residue which consistedessentially of m-methoxy-α-nitrotoluene and dimers of the methyleneketone. Subsequent elution with 5 l. of an n-hexane/ether mixture (9:1)and 5 l. of an n-hexane/ether mixture (4:1) gave, after concentration(finally at 50° C./0.01 Torr), 9.0 g of17β-tert.butoxy-3-methoxy-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-onewhich, according to the NMR spectrum, consisted of a ca 1:1 mixture ofthe two C-6 epimers. By crystallization from 50 ml of isopropylether/n-hexane (1:1) and recrystallization from isopropyl ether, therecould be separated a total of 3.6 g of crystals melting at 115.5°-116.5°C.

EXAMPLE 4

A solution of 7.28 g of m-α-dinitrotoluene in 50 ml of absolutedimethylformamide at 0° C. was treated portionwise within 2 minutes witha total of 1.92 g of a 50% sodium hydride suspension in mineral oil. Tothe red-brown suspension obtained was added dropwise at 0° C. within 30minutes with stirring and gassing with argon a solution of 10.38 g of(+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-onein 65 ml of absolute dimethylformamide. The mixture was stirred in anargon atmosphere firstly for 2 hours at 0° C. and then for a further 3hours at 25° C. The solution was poured on to 400 ml of 0.1-N aceticacid at 0° C. and the resulting emulsion was extracted three times with200 ml of ether. The ethereal extracts were washed with 100 ml of 5%sodium bicarbonate solution, twice with 100 ml of water and dried oversodium sulphate. Filtration and concentration of the filtrate under awater-jet vacuum up to 11 Torr on a bath at 40° C. gave 18.2 g of abrownish resin. The resin was dissolved in 20 ml of ether and thesolution was added to a column of 720 g of silica gel prepared withn-hexane. The column was eluted first with 3 l. of n-hexane. Subsequentelution with 6 l. of a mixture of 9 parts by volume of n-hexane and 1part by volume of ether as well as 2 l. of a mixture of 85 parts byvolume of n-hexane and 15 parts by volume of ether gave, aftercombination of the eluates and concentration (finally at 50° C. and 11Torr), 1.3 g of a residue which consisted mainly of a dimer of themethylene ketone. By elution with 14 l. of n-hexane/ether (85:15) andconcentration, finally at 50° C. and 0.01 Torr, there were obtained 14.6g of 17β-tert.butoxy-3,6-dinitro-9,10-seco-estra-1,3,5(10)-trien-9-one(C- 6 epimeric mixture). By dissolution in 40 ml of isopropyl ether andstorage for 16 hours at 0° C., there were obtained 8.0 g of a pureepimer as light yellow colored crystals melting at 105°-106.5° C.;[α]_(D) ²⁵ = -11° (c = 1.0 in chloroform); NMR (CDCl₃): 1.05 ppm (3H,singlet) C-18-CH₃. The oily residue from the mother liquor consisted ofa mixture of the crystalline isomer melting at 105°-106.5° C. and itsC-8 epimer according to thin-layer chromatography and the NMR spectrum;NMR (CDCl₃): 0.85 ppm (3H, singlet) C-18CH₃.

EXAMPLE 5

8.2 g of(+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-onewere added to a solution of 5.46 g of m-α-dinitrotoluene in 60 ml of0.05-N methanolic sodium methylate and the yellow-orange solutionobtained was allowed to stand for 72 hours at room temperature in anargon atmosphere. The suspension was cooled to 0° C., filtered undervacuum and the residue was washed with 20 ml of ice-cold methanol anddried for 2 hours at 40° C. and 11 Torr to give 9.30 g of light yellowcrystals melting at 103.5°-105° C. The mother liquor and methanolicwashings were combined and concentrated to a volume of 30 ml under awater-jet vacuum on a bath at 40° C. Over a period of 72 hours, anadditional 0.86 g of crystals melting at 104°-105.5° C. separated fromthe solution. The mother liquor was treated with 0.2 ml of glacialacetic acid and concentrated under a water-jet vacuum on a bath at 40°C. The residue was taken up in ether and the ethereal solution waswashed with water and dried over anhydrous sodium sulphate. The residue,3.5 g of a brownish foam, remaining after filtration and concentrationat 40° C. in vacuo up to 11 Torr gave, after chromatography on 175 g ofsilica gel (0.06-2 mm) and elution with 2 l. of a mixture of 4 parts ofn-hexane and 1 part of ether, 0.85 g of dimers of the methylene ketoneand, by subsequent elution with 3 l. of the same solvent mixture, 1.52 gof 17β-tert.butoxy-3,6ξ-dinitro-9,10-seco-estra-1,3,5(10)-trien-9-one.

EXAMPLE 6

A solution of 3.75 g of17β-tert.butoxy-3,6ξ-dinitro-9,10-seco-estra-1,3,5(10)-trien-9-one in 30ml of dimethylformamide was treated with 6 g of 5% palladium/carbon andthe system was evacuated and subsequently shaken in a hydrogenatmosphere. The hydrogen uptake ceased after 5 hours. The catalyst wasfiltered under vacuum, washed with 50 ml of methylene chloride and thefiltrate was concentrated, finally at 80° C. and 0.01 Torr, to give 2.95g of a brown oil. A sample was purified by preparative thin-layerchromatography on silica gel plates. There was obtained3-amino-17β-tert.butoxy-9,10-seco-estra-1,3,5(10)-trien-9-one as an oil;NMR (CDCl₃): 1.0 ppm (3H, singlet) C-18-CH₃.

EXAMPLE 7

A solution of 2.09 g of crystalline17β-tert.butoxy-3,6-dinitro-9,10-seco-estra-1,3,5(10)-trien-9-one in 20ml of dimethylformamide was treated with 3 g of 5% palladium/carbon andthe system was evacuated and shaken in a hydrogen atmosphere until thehydrogen uptake amounted to only 1 ml per 1 minute (3 hours). Thesuspension was filtered under vacuum and the residue was washed with 20ml of methylene chloride and the filtrate diluted with 400 ml of water.The resulting emulsion was extracted with a total of 200 ml of ether.The ethereal solution was washed with water and dried over anhydroussodium sulphate. The residue (1.75 g) remaining after removal of thesolvent on a bath at 40° C. and 11 Torr was diluted with 2 ml ofpyridine, 2 ml of acetic anhydride were added and the solution was leftat room temperature for 1 hour. The mixture was diluted with 50 ml ofwater and the resulting emulsion extracted with 50 ml of ether. Theethereal solution was washed with 10 ml of 1-N hydrochloric acid, with20 ml of a saturated sodium bicarbonate solution and finally with waterto neutrality. The residue obtained after removal of the ether waschromatographed on 72 g of silica gel. Elution with ether gave firstly50 mg of apolar fractions and subsequently a total of 1.42 g of3-acetamino-17β-tert.butoxy-9,10-sec-estra-1,3,5(10)-trien-9-one as anoil; [α]_(D) ⁵⁸⁵ = +26° (c = 0.1 in dioxane); NMR (CDCl₃): 1.02 ppm (3H,singlet) C-18-CH₃. By subsequent elution with a 1:1 mixture of methylenechloride and ether, containing 2% methanol, there were obtained 0.278 gof crystalline product. Recrystallization from methylenechloride/isopropyl ether gave 0.187 g of a homogeneous epimer of3,6-bis(acetamido)-17β-tert.-butoxy-9,10-seco-estra-1,3,5(10)-trienemelting at 248.5°-250.5° C., [α]_(D) ²⁵ = -24° (c = 0.1 in dioxane).

EXAMPLE 8

A solution of 16.7 g of m-methoxy-α-nitrotoluene in 400 ml ofdimethylformamide was treated with 0.5 g of sodium methylate and 26.9 gof (+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one and the mixturewas allowed to stand for 16 hours at room temperature. The yellowsolution was treated wit 0.6 ml of glacial acetic acid and 40 g of 10%palladium/carbon and then shaken in a hydrogen atmosphere. The hydrogenuptake (9.7 l.) was complete after 5 hours. The suspension was filteredunder suction. The residue was washed with 50 ml of dimethylformamideand 30 ml of methylene chloride and the filtrate poured into 4 l. ofwater. The emulsion was extracted with a total of 3 l. of ether and theethereal solution was washed with a total of 3 l. of water andconcentrated on a bath at 50° C. There was obtained crude (+)-17β-tert.butoxy-3-methoxy-9,10-seco-estra-1,3,5(10)-trien-9-one.

EXAMPLE 9

a. A suspension of 4.86 g of m-benzyloxy-α-nitrotoluene in 40 ml ofmethanol was treated with 0.1 g of sodium methylate and 4.73 g of(+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one and thesolution which formed after stirring for 30 minutes was allowed to standfor 72 hours at room temperature. The mixture consisting of two oilyphases was treated with 1 ml of glacial acetic acid and concentrated ina water-jet vacuum on a bath at 40° C. The residue was taken up in 100ml of ether. The solution was washed with 100 ml of water, dried overanhydrous sodium sulphate and, after filtration, concentrated in awater-jet vacuum on a bath at 40° C. The residue, 10.1 g of a yellowoil, was chromatographed on a column of 500 g of silica gel preparedwith n-hexane/ether (19:1). Elution with 6 l. of the same solventmixture gave, after concentration, 1.5 g of a residue from which, aftertreatment with n-hexane, 0.6 g of m-benzyloxy-α-nitrotoluene of meltingpoint 55°-56° C. was isolated. Dimers of the methylene ketone werepresent in the mother liquor. Elution with an additional 2 l. ofn-hexane/ether (19:1) gave, after concentration, 1.8 g of a residue. Twocrystallizations of the residue from hexane gave 1.1 g of a homogeneousepimer of3-benzyloxy-17β-tert.butoxy-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-onemelting at 97.5°-99.5° C., [α]_(D) ²⁵ = +9.4° (c = 1.0 in chloroform);NMR (CDCl₃): δ 1.02 ppm (3H, singlet) C-18-CH₃. Elution with 6 l. ofn-hexane/ether (19:1) and with 4 l. of hexane/ether (9:1)yielded, afterconcentration, 6.2 g of a residue. Recrystallization of the residue fromhexane gave 5.6 g of a crystalline product melting at 86°-98° C which,according to thin-layer chromatography and NMR spectroscopy, consistedof a mixture of the aforementioned nitro compound melting at 97.5°-99.5°C. and the C-6 epimer; NMR (CDCl₃): δ 0.80 ppm (3H, singlet) C-18-CH₃.

b. A solution of 6.05 g of C-6 epimeric mixture of3-benzyloxy-17β-tert.butoxy-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-onein 50 ml of dimethylformamide was treated with 9 g of 10%palladium/carbon and the system was evacuated and subsequently shaken ina hydrogen atmosphere. 1.8 g of hydrogen were taken up within 5 hours.The catalyst was filtered under suction. The filtrate was added to 0.5l. of water and the emulsion was extracted with a total of 0.5 l. ofether. The ethereal solution was washed with water, dried over anhydroussodium sulphate and, after filtration, concentrated in a water-jetvacuum on a bath at 40° C. up to 11 Torr. The crystalline residue (3.9g) gave, after crystallization from methylene chloride/isopropyl ether,2.7 g of(+)-17β-tert.butoxy-3-hydroxy-9,10-seco-estra-1,3,5(10)-trien-9-onemelting at 187°-188° C.; [α]_(D) ²⁵ = +28.6° (c = 1.0 in chloroform).

EXAMPLE 10

a. A solution of 1.97 g of 3,5-dimethoxy-α-nitrotoluene in 20 ml ofmethanol was treated with 60 mg of sodium methylate and subsequentlyadded to 2.6 g of (+)- 1β-tert.butoxy-3aα ,6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one. The mixture was stirred for 30minutes and the solution was allowed to stand for 72 hours at roomtemperature. After the addition of 0.1 ml of glacial acetic acid, thesolution was concentrated in a water-jet vacuum on a bath at 40° C. Theresidue was taken up in 60 ml of ether and washed with a total of 100 mlof water. After drying over anhydrous sodium sulphate, filtration andconcentration in a water-jet vacuum on a bath at 40° C. up to 11 Torr,there were obtained 4.7 g of a yellow oil. This oil was chromatographedon a column of 250 g of silica gel prepared with n-hexane/ether (19:1).Elution with 6.5 l. of the same solvent mixture gave, afterconcentration, 0.9 g of a residue consisting of dimers of the methyleneketone and 3,5-dimethoxy-α-nitrotoluene. Elution with an additional 2.5l. of the foregoing solvent mixture yielded 1.2 g of a residue. Twocrystallizations of this residue from pentane gave 0.75 g of ahomogeneous epimer of17β-tert.butoxy-1,3-dimethoxy-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-onemelting at 90.5°-91° C.; [α ]_(D) ²⁵ = +34.7° (c = 1.0 in methanol); NMR(CDCl₃): δ 1.03 ppm (3H, singlet) C-18-CH₃. Elution with 6 l. ofhexane/ether (9:1) gave, after concentration, 2.2 g of an oily residuewhich, according to NMR spectroscopy, consisted of a mixture of theforegoing nitro compound melting at 90.5°-91° C. and the C-6 epimer; NMR(CDCl₃): δ 0.85 ppm (3H, singlet) C-18-CH₃.

b. The17β-tert.butoxy-1,3-dimethoxy-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-oneobtained according to paragraph (a) was hydrogenated to give17β-tert.butoxy-1,3-dimethoxy-9,10-seco-estra-1,3,5(10)-trien-9-one bythe method described in paragraph (b) of Example 9.

EXAMPLE 11

a. A solution of 3.34 g of m-methoxy-α -nitrotoluene in 40 ml ofmethanol was treated with 0.1 g of sodium methylate and 5 g of(+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-ethyl-4-methylene-indan-5(4H)-oneand allowed to stand for 72 hours at room temperature. After theaddition of 1 ml of glacial acetic acid, the yellow solution wasconcentrated in a water-jet vacuum on a bath at 40° C. The residue wastaken up in 150 ml of ether and the solution was washed with 100 ml ofwater and then dried over anhydrous sodium sulphate. The residue, 8.5 gof a yellow resin, remaining after concentration (finally at 40° C and11 Torr), was chromatographed on a column of 2 kg of silica gel preparedwith hexane/ether (9:1). Elution with the same solvent mixture gave amixture of m-methoxy-α-nitrotoluene and dimers of the methylene ketoneand then 6.81 g of the C-6 epimer mixture of17β-tert.-butoxy-3-methoxy-18-methyl-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-one.Two crystallizations from methanol at -20° C. yielded 3.55 g of ahomogeneous epimer melting at 113°-114° C.; [α]_(D) ²⁵ = +30° (c = 1.034in dioxane).

b. A solution of 1.3 g of the 6 epimeric C- mixture of17β-tert.-butoxy-3-methoxy-18-methyl-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-onein 12 ml of dimethylformamide was treated with 1.25 g of 5%palladium/carbon. The system was evacuated and shaken in a hydrogenatmosphere. 0.31 l. of hydrogen was taken up within 3 hours. Thecatalyst was filtered under suction. The filtrate was treated with 130ml of water and the emulsion extracted with a total of 150 ml of ether.The ethereal solution was washed with water, dried over anhydroussulphate and, after filtration, concentrated in a water-jet vacuum on abath at 40° C. The residue was chromatographed on a column of 30 g ofsilica gel in ether. Elution with 400 ml of ether gave, afterconcentration and drying for 30 minutes at 40° C. and 0.01 Torr, 1.0 gof (+)-17β-tert.butoxy-3-methoxy-18-methyl-9,10-seco-estra-1,3,5(10)-trien-9-oneas an oil; [α]_(D) ²⁵ = +13° (c = 0.102 in dioxane).

EXAMPLE 12

a. A suspension of 2.43 g of m-benzyloxy-α -nitrotoluene in 20 ml ofmethanol was treated with 54 mg of sodium methylate and 2.5 g of(+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-ethyl-4-methylene-indan-5(4H)-one and the solutionobtained after stirring for 10 minutes was allowed to stand for 72 hoursat room temperature. After treatment with 0.1 ml of glacial acetic acid,the suspension was concentrated in a water-jet vacuum on a bath at 40°C. The solid residue obtained was taken up in 100 ml of ether and thesolution washed with 150 ml of water and dried over anhydrous sodiumsulphate. The residue (5.08 g) remaining after concentration (finally at40° C. and 11 Torr), gave, from methanol, 3.5 g of the crystalline C-6epimeric mixture of3-benzyloxy-17β-tert.butoxy-18-methyl-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-one.Three crystallizations from acetone/hexane gave a pure epimer; meltingpoint 134°-135° C.; [α]_(D) ²⁵ = -1.2° (c = 0.996 in chloroform).

b. The3-benzyloxy-17β-tert.butoxy-18-methyl-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-oneobtained according to paragraph (a) was hydrogenated to give17β-tert.butoxy-3-hydroxy-18-methyl-9,10-seco-estra-1,3,5(10)-trien-9-oneby the method described in paragraph (b) of Example 9.

EXAMPLE 13

a. A solution of 0.99 g of 3,5-dimethoxy-α-nitrotoluene in 10 ml ofmethanol was treated with 30 mg of sodium methylate and 1.25 g of(+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-ethyl-4-methylene-indan-5(4H)-oneand the mixture was stirred at room temperature for 88 hours. Aftertreatment with 0.1 ml of glacial acetic acid, the mixture wasconcentrated in a water-jet vacuum on a bath at 40° C., the residue wastaken up in 50 ml of ether and the solution washed with a total of 100ml of water. After drying over anhydrous sodium sulphate, filtration andconcentration (finally at 40° C. and 11 Torr), there were obtained 2.3 gof an oil. The oil was chromatographed on a column of 450 g of silicagel prepared with hexane/ether (14:1). Elution with the same solventmixture gave 1.76 g of the C-6 epimeric mixture of17β-tert.butoxy-1,3-dimethoxy-18-methyl-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-one as a resin;[α]_(D) ²⁵ = +9° (c = 0.1 in dioxane).

b. The17β-tert.butoxy-1,3-dimethoxy-18-methyl-6-nitro-9,10-seco-estra-1,3,5(10)-trien-9-oneobtained according to paragraph (a) was hydrogenated to give17β-tert.butoxy-1,3-dimethoxy-18-methyl-9,10-seco-estra-1,3,5(10)-trien-9-oneby the method described in paragraph (b) of Example 9.

EXAMPLE 14

a. A suspension of 0.73 g of m-α -dinitrotoluene in 8 ml of methanol wastreated with 22 mg of sodium methylate and 1 g of(+)-1β-tert.butoxy-3aα,6,7,7a-tetrahydro-7aβ-ethyl-4-methylene-indan-5(4H)-oneand the solution formed after stirring for 30 minutes was allowed tostand for 72 hours at room temperature. The suspension was filteredunder suction after cooling to -5° C. The residue, after crystallizationfrom isopropyl ether, yielded 0.62 g of a homogeneous epimer of17β-tert.butoxy-3,6-dinitro-18-methyl-9,10-seco-estra-1,3,5(10)-trien-9-onemelting at 108°-109° C.; [α]_(D) ²⁵ = +4° (c = 0.1 in dioxane). Themother liquors were combined, treated with 0.1 ml of glacial acetic acidand concentrated in a water-jet vacuum on a bath at 40° C. The residuewas chromatographed on a column of 200 g of silica gel prepared withhexane/ether (14.1). Elution with the same solvent mixture gave, afterconcentration, 0.55 g of nitro adduct in the form of the C-6 epimericmixture.

b. A suspension prepared from 0.98 g of(+)-17β-tert.butoxy-3,6-dinitro-18-methyl-9,10-seco-estra-1,3,5(10)-trien-9-one,1.5 g of 5% palladium/carbon and 7.5 ml of dimethylformamide was shakenat room temperature in a hydrogen atmosphere. After completion of thehydrogen uptake (0.395 l. in 3.5 hours), the catalyst was filtered undersuction and the filtrate concentratd on a bath at 50° C. at 0.01 Torr.The residue, which solidified upon cooling, gave, afterrecrystallization from ether/pentane and then from methanol, 0.4 g of(+)-3-amino-17β-tert.butoxy-18-methyl-9,10-seco-estra-1,3,5(10)-trien-9-onemelting at 119°-120° C.; [α]_(D) ²⁵ = +12° (c = 0.98 in chloroform).

EXAMPLE 15

A solution of 1.56 g (+)-17β-tert.butoxy-3-methoxy-9,10-seco-estra-1,3,5(10)-trien-9-one wastreated over a period of 3 minutes with 30 ml of 10-N hydrochloric acidwith vigorous stirring under nitrogen. The mixture was stirred for 3hours at room temperature for 30 minutes with ice-cooling and was thenfiltered. The precipitate was washed three times with 15 ml-portions ofwater and dried under reduced pressure to give(+)-17β-tert.butoxy-3-methoxy-estra-1,3,5(10)-9(11)-tetraene melting at133°-134° C. (from methanol).

EXAMPLE 16

0.679 g of (+)-17β-tert.butoxy-3-methoxy-estra-1,3,5(10)-9(11)-tetraenewas hydrogenated at atmospheric pressure in 25 ml of ethyl acetate inthe presence of 0.2 g of pre-equilibrated 5% palladium/carbon catalyst.After stirring for 1.5 hours, 50 ml of hydrogen was absorbed. Thecatalyst was filtered and washed with ethyl acetate. Evaporation gave17β-tert.butoxy-3-methoxy-estra-1,3,5(10)-trien as a light-yellow oilmelting at 91°-92.5° C.

We claim:
 1. A process for the preparation of a compound of the formula##STR14## wherein R¹ and R² independently are hydrogen, amino, OR⁵,OCOR⁶ or NHCOR⁵ wherein R⁵ is hydrogen or lower alkyl and R⁶ is loweralkyl or phenyl; R³ is lower alkyl; R⁴ is oxo, ##STR15## wherein R¹³ islower alkyl, lower alkoxy-lower alkylene, tetrahydropyranyl orteytrahydrofuryl, R¹⁴ is lower alkyl or phenyl and R¹⁵ and R¹⁶ are loweralkyl or taken together form lower alkylene or arylene of 6 to 10 carbonatoms, and n is 1 or 2, which comprises the steps ofa. condensing acompound of the formula ##STR16## wherein R³, R⁴ and n are ashereinbefore defined with a compound of the formula ##STR17## wherein R⁷and R⁸ independently and respectively are R¹ and R², nitro, benzyloxy,dephenylmethoxy or triphenylmethoxy, and R⁹ is hydrogen, cyano or COOR¹⁰wherein R¹⁰ is lower alkyl or benzyl, in the presence of a base to givea compound of the formula ##STR18## wherein R³, R⁴, R⁷, R⁸ and n are ashereinbefore defined; b. saponifying and then decarboxylating a compoundobtained in step (a) when R⁹ is cyano or COOR¹⁰ wherein R¹⁰ is ahereinbefore defined in the presence of alkali and then in the presenceof acid to give a compound of the formula ##STR19## wherein R³, R⁴, R⁷,R⁸ and n are as hereinbefore defined, and c. hydrogenating a compoundobtained in step (b) in the presence of a noble metal or nickelcatalyst.
 2. The process according to claim 1 wherein the base of step(a) is present in a catalytic amount.
 3. The process according to claim2 wherein the catalytic amount is 1 to 10 mole percent.
 4. The processof claim 1 wherein R³ is lower alkyl; R⁴ is ##STR20## wherein R¹³ islower alkyl or lower alkoxy-lower alkylene; R⁷ is nitro or OR⁵ whereinR⁵ is lower alkyl; R⁸ is hydrogen or OR⁵ wherein R⁵ is lower alkyl; R⁹is hydrogen and n is 1 or
 2. 5. The process of claim 4 wherein R³ ismethyl or ethyl; R¹³ is tert.-butyl or methoxymethylene, R⁵ is methyl;and n is
 1. 6. A process for the preparation of a compound of theformula ##STR21## wherein R¹ and R² independently are hydrogen, amino,OR⁵, OCOR⁶ or NHCOR⁵ wherein R⁵ is hydrogen or lower alkyl and R⁶ islower alkyl or phenyl; R³ is lower alkyl; R⁴ is oxo, ##STR22## whereinR₁₃ is lower alkyl, lower alkoxy-lower alkylene, tetrahydropyranyl ortetrahydrofuryl, R¹⁴ is lower alkyl or phenyl and R¹⁵ and R¹⁶ are loweralkyl or taken together form lower alkylene or arylene of 6 to 10 carbonatoms, and n is 1 or 2,which comprises the steps of a. condensing acompound of the formula ##STR23## wherein R³ is lower alkyl; R⁴ is oxo,##STR24## wherein R¹³ is lower alkyl, lower alkoxy-lower alkylne,tetrahydropyranyl or tetrahydrofuryl, R¹⁴ is lower alkyl or phenyl andR¹⁵ and R¹⁶ are lower alkyl or taken together form lower alkylene orarylene of 6 to 10 carbon atoms; X is OR¹¹, N(R¹²)₂, SR¹¹, N⁺(R¹²)₃,##STR25## or S⁺(R¹²)₂ wherein R¹¹ is hydrogen, lower alkyl, acetyl orbenzoyl, R¹² is lower alkyl, and m is 1 or 2; and n is 1 or 2,with acompound of the formula ##STR26## wherein R⁷ and R⁸ independently andrespectively are R¹ and R², nitro, benzyloxy, diphenylmethoxy ortriphenylmethoxy, and R⁹ is hydrogen, cyano or COOR¹⁰ wherein R¹⁰ islower alkyl or benzyl, in the presence of a base to give a compound ofthe formula ##STR27## wherein R³, R⁴, R⁷, R⁸ and n are as hereinbeforedefined; b. saponifying and then decarboxylating a compound obtained instep (a) when R⁹ is cyano or COOR¹⁰ wherein R¹⁰ is as hereinbeforedefined in the presence of alkali and then in the presence of acid togive a compound of the formula ##STR28## wherein R³, R⁴, R⁷, R⁸, R⁹ andn are as hereinbefore defined, and c. hydrogenating a compound obtainedin step (b) in the presence of a noble metal or nickel catalyst.
 7. Theprocess according to claim 6 wherein R³ is lower alkyl; R⁴ is ##STR29##wherein R¹³ is lower alkyl or lower alkoxy-lower alkylene; R⁷ is nitroor OR⁵ wherein R⁵ is lower alkyl; R⁸ is hydrogen or OR⁵ wherein R⁵ islower alkyl; R⁹ is hydrogen and n is 1 or
 2. 8. The process of claim 7wherein R³ is methyl or ethyl; R¹³ is tert.-butyl or methoxymethylene,R⁵ is methyl; and n is 1.